Arylsulfatase A, Fibroblasts
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by a deficiency of arylsulfatase A. MLD follows an autosomal recessive inheritance pattern and is caused by mutations in the ARSA gene. Deficiency of arylsulfatase A leads to the accumulation of sulfatides (both galactosyl and lactosyl sulfatide) in the white matter of the central nervous system, the peripheral nervous system, and visceral organs including the kidney and gallbladder. In patients with MLD, sulfatides are excreted in excessive amounts in the urine.
The 3 clinical forms of MLD are late-infantile, juvenile, and adult, which are categorized based on age of onset. All forms result in progressive neurologic changes and leukodystrophy demonstrated on magnetic resonance imaging. Late-infantile MLD typically presents between 6 months to 2 years of age with hypotonia, clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration occurs and most patients die within 5 years of the diagnosis. Juvenile MLD is characterized by onset between 4 to 14 years. Typical presenting features are behavior problems, declining school performance, clumsiness, and slurred speech. Neurodegeneration occurs at a somewhat slower and more variable rate than the late-infantile form. Adult MLD has an onset after puberty and can be as late as the fourth or fifth decade. Presenting features are often behavior and personality changes, including psychiatric symptoms; clumsiness, neurologic symptoms, and seizures are also common. The disease course has variable progression and may occur over 2 to 3 decades. The disease prevalence is estimated to be approximately 1 in 100,000.
Extremely low arylsulfatase A levels have been found in some clinically normal parents and other relatives of MLD patients. These individuals do not have metachromatic deposits, and their urine content of sulfatide is normal. Individuals with this "pseudodeficiency" have been recognized with increasing frequency among patients with other apparently unrelated neurologic conditions as well as among the general population. This has been associated with fairly common polymorphisms in the ARSA gene, which leads to low expression of the enzyme (5%-20% of normal). These patients can be difficult to differentiate from actual MLD patients. Additional studies, such as molecular genetic testing of ARSA (ARSAS / ARSA Gene, Full Gene Analysis), urinary excretion of sulfatides (CTSA / Ceramide Trihexoside/Sulfatide Accumulation in Urine Sediment, Urine) and/or histological analysis for metachromatic lipid deposits in nervous system tissue are recommended to confirm a diagnosis.
Current treatment options for MLD are usually focused on managing disease manifestations such as seizures. Bone marrow transplantation remains controversial, and the effectiveness of enzyme replacement therapy may be limited due to difficulties crossing the blood-brain barrier. Other treatments under ongoing investigation include hematopoietic stem cell transplantation and fetal umbilical cord blood transplantation.
Detection of metachromatic leukodystrophy
Arylsulfatase A is deficient in metachromatic leukodystrophy and multiple sulfatase deficiency.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test is not suitable for carrier status detection due to both analytical and unusual genetic variation. Individuals with pseudodeficiency of arylsulfatase A may have decreased enzyme activity and are not clinically affected with metachromatic leukodystrophy.
Arylsulfatase A is also deficient in individuals with multiple sulfatase deficiency.
This disorder is distinct from conditions caused by deficiencies of arylsulfatase B (Maroteaux-Lamy disease) and arylsulfatase C (steroid sulfatase deficiency).
Interfering factors include lack of viable cells, bacterial contamination, failure to transport tissue in an appropriate media, excessive transport time, and exposure of the specimen to temperature extremes (freezing or >30 degrees C).
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
> or =4.25 nmol/min/mg protein
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Jaeken J, Gieselmann V, von Figura K: Metachromatic leukodystrophy. In Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMMBID). Edited by D Valle, et al. McGraw-Hill Companies, Inc. Available from URL: http://www.ommbid.com/OMMBID/a/c.html/lysosomal_disorders/metachromatic_leukodystrophy/abstract
2. Fluharty AL: Arylsulfatase A Deficiency. In GeneReviews. Edited by RA Pagon, TD Bird, CR Dolan, et al: Seattle (WA): University of Washington, Seattle, 1993. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1130/
3. Mahmood A, Berry J, Wenger D, et al: Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol 2010;25(5):572-580